Pioglitazone Hydrochloride Tablets

This product belongs to the thiazolidinedione class of oral antidiabetic drugs. It is a highly selective agonist of peroxisome proliferator-activated receptor gamma (PPARgamma). It controls blood sugar levels by increasing peripheral and liver insulin sensitivity. Its main mechanism of action is to activate PPAPgamma nuclear receptors in tissues such as fat, skeletal muscle and liver where insulin acts, thereby regulating the transcription of insulin-responsive genes and controlling the production, transport and utilization of blood sugar.

The main ingredient of this product is pioglitazone hydrochloride, and its chemical name is (plusmn;) 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione hydrochloride.

For patients with type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM), pioglitazone hydrochloride can be combined with diet control and physical exercise to improve blood sugar control. Pioglitazone hydrochloride can be used alone, or in combination with sulfonylurea, metformin or insulin when diet control, physical exercise and monotherapy cannot satisfactorily control blood sugar.

Pioglitazone hydrochloride should be taken once daily, regardless of whether the medication is taken during meals. Diabetes treatment should be individualized. HbAIC is a better indicator of long-term blood sugar control than FBC alone for evaluating treatment response. HbAIC reflects the blood sugar status over the past 2 to 3 months. In clinical application, we recommend that patients should be treated with pioglitazone hydrochloride for a sufficient period of time (3 months) to evaluate changes in HbAIC unless blood sugar control deteriorates. 1. Monotherapy When diet control and physical exercise alone are insufficient to control blood sugar, pioglitazone hydrochloride monotherapy can be used, with an initial dose of 15 mg or 30 mg once a day. If the response to the initial dose is poor, the dose can be increased to 45 mg once a day. If the patient does not respond well to monotherapy, combination therapy should be considered. 2. Combination therapy (1) Sulfonylurea: When used in combination with sulfonylurea drugs, the initial dose of pioglitazone hydrochloride can be 15 mg or 30 mg once a day. When starting pioglitazone hydrochloride treatment, the sulfonylurea dose can remain unchanged. When the patient develops hypoglycemia, the sulfonylurea dose should be reduced. (2) Metformin: When used in combination with metformin, the initial dose of pioglitazone hydrochloride can be 15 mg or 30 mg once a day. When starting pioglitazone hydrochloride treatment, the metformin dose can remain unchanged. Generally speaking, when used in combination with metformin, the metformin dose does not need to be reduced and will not cause hypoglycemia. (3) Insulin: When used in combination with insulin, the initial dose of pioglitazone hydrochloride can be 15 mg or 30 mg once a day. When starting pioglitazone hydrochloride treatment, the insulin dose can remain unchanged. For patients taking pioglitazone hydrochloride and insulin in combination, when hypoglycemia occurs or the plasma glucose concentration drops below 100 mg/dL, the insulin dose can be reduced by 10% to 25%. Further individualized adjustments are made based on blood glucose results. 3. The maximum recommended dose of pioglitazone hydrochloride should not exceed 45 mg once a day, because no placebo-controlled clinical studies have been conducted for medications exceeding this dose. No placebo-controlled clinical studies have been conducted for combined medications exceeding 30 mg. 4. For patients with renal insufficiency, the dose does not need to be adjusted (see [Pharmacokinetics], Special Populations, Renal Insufficiency). If the patient has clinical manifestations of active liver disease or elevated serum transaminase levels (ALT exceeds 2.5 times the upper limit of normal) before treatment begins, pioglitazone hydrochloride treatment should not be started (see [Precautions], General, Effects on the Liver and [Pharmacokinetics], Special Populations, Hepatic Insufficiency). All patients should have liver enzymes monitored before starting pioglitazone hydrochloride treatment and during treatment (see [Precautions], General, Effects on the Liver). There is currently no data on the use of pioglitazone hydrochloride in patients under 18 years of age, so pioglitazone hydrochloride should not be used in pediatric patients. 5. There is currently no data on the combined use of pioglitazone hydrochloride and other thiazolidinediones.

According to foreign literature reports: 1. When pioglitazone hydrochloride is used in combination with sulfonylureas (N=373), metformin (N=168) or insulin (N=379), the types of clinical adverse reactions are similar to those of pioglitazone hydrochloride monotherapy, with the only exception that when used in combination with insulin, the incidence of edema increases (pioglitazone: 15%, placebo: 7%). The incidence of withdrawal from clinical trials due to adverse reactions (except hyperglycemia) is similar in the placebo group (2.8%) and the pioglitazone hydrochloride group (3.3%). 2. When used in combination with sulfonylureas or insulin, patients have experienced mild to moderate hypoglycemia. When used in combination with a sulfonylurea drug, the incidence of hypoglycemia in the placebo group was 1%, and in the pioglitazone hydrochloride group was 2%. When used in combination with insulin, the incidence of hypoglycemia in the placebo group was 5%, in the 15 mg pioglitazone hydrochloride group was 8%, and in the 30 mg pioglitazone hydrochloride group was 15% (see [Precautions], General, Hypoglycemia). 3. Double-blind studies conducted in the United States showed that when used as monotherapy, the incidence of anemia in patients treated with pioglitazone hydrochloride was 1.0%, while that in patients treated with placebo was 0.0%. When used in combination with insulin, the incidence of anemia in the pioglitazone hydrochloride group was 1.6%, while that in patients treated with placebo was 1.6%. When used in combination with sulfonylureas, the incidence of anemia in the pioglitazone hydrochloride group was 0.3%, while that in patients treated with placebo was 1.6%. When used in combination with metformin, the incidence of anemia in the pioglitazone hydrochloride group was 1.2%, while that in patients treated with placebo was 0.0%. 4. All clinical trials conducted in the United States showed that the incidence of edema in patients in the pioglitazone hydrochloride group was higher than that in the placebo group. When used as monotherapy, 4.8% of patients treated with pioglitazone hydrochloride had edema, while that in the placebo group was 1.2%. When used in combination with insulin, the incidence of edema was highest (15.3% in the pioglitazone hydrochloride group and 7.0% in the placebo group). All cases were only mild or moderate (see [Precautions], General, Edema). Laboratory Abnormalities 1. Hematology: Pioglitazone hydrochloride may cause a decrease in hemoglobin and hematocrit. For all clinical studies, the mean hemoglobin of patients treated with pioglitazone hydrochloride decreased by 2% to 4%. In general, such changes occur in the first 4 to 12 weeks of treatment and are relatively stable thereafter. These changes may be related to the increase in plasma volume caused by pioglitazone hydrochloride, and no important clinical hematological significance has been found so far. 2. Serum aminotransferase levels: In placebo-controlled clinical trials conducted in the United States, a total of 4 (0.26%) of 1526 pioglitazone hydrochloride-treated patients and 2 (0.25%) of 793 placebo-treated patients had ALTge; 3 times the upper limit of normal. In all clinical studies conducted in the United States, a total of 11 (0.43%) of 2561 pioglitazone hydrochloride-treated patients had ALTge; 3 times the upper limit of normal. All patients with follow-up values had reversible increases. In the group treated with pioglitazone hydrochloride, the mean values of bilirubin, AST, ALT, alkaline phosphatase and CCT at the last visit were lower than the mean values at baseline. In the United States, less than 0.12% of patients withdrew from clinical trials due to abnormal liver function. 3. In clinical trials with informed consent, no constitution-specific drug reactions leading to liver failure were observed (see [Precautions], General, Effects on the Liver). 4. CPK level: Sporadic, transient increases in creatine phosphokinase (CPK) levels were observed during necessary laboratory tests in clinical trials. Seven patients had a single, isolated increase in CPK (more than 10 times the upper limit of normal, with values ranging from 2150 to 8610). Of the seven patients, five continued to receive pioglitazone hydrochloride treatment, and two had CPK increases after the end of the trial, and these increases were recovered. There were no obvious clinical sequelae. The relationship between this situation and pioglitazone hydrochloride treatment has not yet been clarified. 5. Macular edema: There are reports after the overseas market launch that taking thiazolidinediones including pioglitazone can cause or aggravate (diabetic) macular edema and decreased vision, but the frequency of occurrence is very rare. It is not yet clear whether macular edema is directly related to taking pioglitazone. If a patient has decreased vision, the doctor should consider the possibility of macular edema. Diabetic patients should receive regular eye examinations by ophthalmologists. In addition, regardless of whether diabetic patients are receiving treatment or have other physical examination abnormalities, they should be examined by an ophthalmologist as soon as any visual symptoms occur. 6. Fractures: In a randomized clinical trial of type 2 diabetes patients (average course of 9.5 years) abroad, researchers noticed an increased incidence of fractures in female patients taking pioglitazone. During the average follow-up of 34.5 months, the incidence of fractures in female patients in the pioglitazone group was 5.1% (44/870), while it was only 2.5% (23/905) in the placebo group. This difference appeared one year after the start of treatment and persisted throughout the study. Fractures in female patients were non-vertebral fractures, including lower extremities and distal upper extremities. The fracture rate in male patients treated with pioglitazone was 1.7% (30/1735), which was not significantly increased compared to 2.1% (37/1728) in the placebo group. When caring for patients treated with pioglitazone, especially female patients, the risk of fracture should be considered and attention should be paid to assessing and maintaining bone health according to current standards of care.

Pioglitazone hydrochloride is contraindicated in patients with known hypersensitivity to this product or any of its ingredients.

Precautions for children: It is still unclear whether pioglitazone hydrochloride is safe and effective for children. Precautions for pregnancy and lactation: Pregnant women: Pregnancy type C. During organogenesis, rats were given 80 mg/kg orally and rabbits were given 160 mg/kg orally (based on mg/m2, approximately 17 times and 40 times the maximum recommended oral dose for humans, respectively), and no teratogenicity was observed with pioglitazone. When rats were given oral doses of more than 30 mg/kg/day (based on mg/m2, approximately equivalent to 10 times the maximum recommended oral dose for humans), delayed labor and embryotoxicity (manifested as increased post-implantation abortions, delayed development, and decreased birth weight) were observed. No functional or behavioral toxicity was observed in the offspring of rats. Embryotoxicity was observed when rabbits were given oral doses of 160 mg/kg (based on mg/m2, approximately equivalent to 40 times the maximum recommended oral dose for humans). When rats were given oral doses of 10 mg/kg and above (approximately 2 times the maximum recommended oral dose for humans, based on mg/m2) during late pregnancy and lactation, their offspring had reduced body weight and postnatal growth retardation. In women, there are no adequate and well-controlled studies, and pioglitazone hydrochloride should be used during pregnancy only when the potential benefits to the fetus outweigh the potential risks. Because the available data strongly suggest that dysglycemia during pregnancy is associated with increased congenital anomalies and neonatal morbidity and mortality, most experts recommend that insulin be used during pregnancy to try to control blood sugar to normal levels. Lactating mothers: In lactating rats, pioglitazone is secreted into breast milk. It is not clear whether humans can secrete pioglitazone hydrochloride into human milk. Because many drugs are secreted into breast milk, women who are breastfeeding should not use pioglitazone hydrochloride. Elderly precautions: In placebo-controlled clinical trials of pioglitazone hydrochloride, approximately 500 patients were aged 65 years and older. There was no significant difference in the efficacy and safety of pioglitazone hydrochloride between these patients and younger patients.

1. When used in combination with ethinyl estradiol and norethindrone, the plasma concentration of the two hormones can be reduced by about 30%. 2. This product has no effect on glipizide, digoxin, warfarin and metformin. 3. CYP3A4 has a certain effect on the metabolism of this product. 4. Ketoconazole can significantly inhibit the metabolism of this product in vitro. 5. No drug-induced tumors were found in other organs except the bladder.

Keep away from light and store in sealed container.

15 mg (based on pioglitazone)

36 months.